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  Intra-tracheal application of vascular endothelial growth factor (vegf) for the prevention of lung damages caused by hperoxiaUSPTO Application #: 20060040860Title: Intra-tracheal application of vascular endothelial growth factor (vegf) for the prevention of lung damages caused by hperoxia Abstract: The invention relates to the field of pulmonary diseases that are related to oxygen provision that is higher than physiological (hyperoxia) and to the use of vascular endothelial growth factor (VEGF) for treatment and prevention. Hyperoxic exposure causes a direct cellular damage in the lung and disturbs lung development. The effect becomes clinically prominent by the development of acute or chronic lung disease. There is a need for a pharmaceutical to prevent oxygen induced lung injuries. VEGF is not only a cellular survival factor but also important for lung development. The oxygen concentration regulates pulmonary VEGF expression, with a suppression during hyperoxia. Low pulmonary VEGF concentrations are responsible for oxygen induced effects. According to the present invention VEGF is used as a medicament for the treatment and/or prevention of pulmonary diseases or conditions that are related to high concentrations of inspired oxygen. (end of abstract) Agent: Rothwell, Figg, Ernst & Manbeck, P.C. - Washington, DC, US Inventors: Mario Ruediger, Edda Tschirch, Bernd Ruestow USPTO Applicaton #: 20060040860 - Class: 514012000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 25 Or More Peptide Repeating Units In Known Peptide Chain Structure The Patent Description & Claims data below is from USPTO Patent Application 20060040860. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to the field of pulmonary diseases or conditions that are related to a deregulation of the oxygen provision and more specifically to the use of vascular endothelial growth factor (VEGF) for the treatment and prevention of these pulmonary diseases or conditions. The pulmonary diseases or conditions treated or prevented, respectively, are caused by high concentrations of inspired oxygen (hyperoxia). [0002] Oxygen is the basic requirement for human life. However, in case that oxygen is used at supra-physiological concentrations it can also damage the human organism. For example, oxidative stress can cause acute and chronic lung injury. The prolonged exposure to a high concentration of oxygen, such as during mechanical ventilation, represents a necessary life-saving therapy for critically ill patients, but does also induce oxidative stress to the lung and causes pulmonary oxygen toxicity. Due to hyperoxia, i.e. the abnormal increase in the amount of inspired oxygen, the lungs can be acutely injured, subsequently leading to chronic damages of the lungs. To develop therapeutic strategies that can prevent these injuries, the underlying pathways of hyperoxia-induced pulmonary damage have to be understood. [0003] In preterm infants, a "relative hyperoxic" exposure occurs post-nataly. Normal development in utero takes place at low oxygen concentration. Exposure of the preterm infant to room air (oxygen concentration of 21%) causes a higher oxygen concentration than during fetal life. In this term the "relative hyperoxic" condition represents a higher oxygen concentration than under normal physiological situations. Since many developmental processes depend on the oxygen concentration, an alteration of normal development can be expected. [0004] Especially during long lasting hyperoxic exposure a direct cellular damage occurs in the lung accompanied by a destruction of the alveolar epithelium, perturbed gas exchange and development of a lung edema (1). Furthermore, hyperoxia induces apoptotic changes (leading to cellular death) in the lung by either activating or inhibiting different cytokines (2). If other damaging factors occur simultaneously, such as mechanical ventilation with baro- or volutrauma or a vitamin E deficiency, an imbalance of the oxidative/anti-oxidative system will lead to an increased apoptosis and a subsequent damage of pulmonary cells (3). [0005] The hyperoxia-induced damage of the lung becomes clinically prominent by the development of an acute or chronic lung disease. High concentrations of inspired oxygen facilitate the progress of the acute respiratory distress syndrome (ARDS) in adults. In the premature lung of the preterm infant a long-term mechanical ventilation and highly concentrated oxygen supplementation lead to the development of a chronic lung disease, the broncho-pulmonary dysplasia (BPD) (4). [0006] 1.8% of all neonates suffer from a respiratory insufficiency that requires mechanical ventilation and oxygen supplementation. All together about 80,000 neonates per year are affected in USA. Whereas respiratory insufficiency is only a minor problem in term infants, almost all very preterm infants suffer from respiratory distress. Even though it was possible to decrease the lethality of the extremely premature infants, the incidence of chronic diseases--particularly of the lungs--remained unchanged in preterm infants (5). The incidence of BPD is about 40-60% of all VLWB preterm neonates (<1500 g weight at birth, VLBW=very low birth weight infants) (6-8). Since there are about 55,000 VLWB preterm neonates per year in USA, about 27,500 infants will develop a BPD each year. Due to the chronic pulmonary damage the initial length of stay in the hospital is significantly prolonged. The subsequent costs for the therapy of infants with chronic lung disease are estimated to be about 1 million for each affected preterm neonate (9). [0007] It is more difficult to estimate the frequency of oxygen-induced pulmonary damages in adults. Acute respiratory distress syndrome (ARDS) consist of a variety of pulmonary diseases that lead to severe pulmonary changes requiring at least some ventilatory support. This syndrome is sometimes also called adult respiratory distress syndrome, although it can occur in children. Typical histological signs of ARDS are fluid accumulation, inflammation and cellular damage in the lung. Due to these changes, systemic oxygenation is deteriorated and thus, supplemental oxygen is required. However, ARDS is partially triggered by an oxygen-associated toxicity (10). Due to the great variety of diseases that are associated with ARDS, great variations exist regarding the incidence of ARDS. In 1972 there was an incidence of 75 per 100,000 adults. However, recent studies assume a frequency of about 15 per 100,000 adults (11). [0008] A major factor in lung vascular development is vascular endothelial growth factor (VEGF), which had first been described as a growth and survival factor of the vascular endothelium and hematopoetic stem cells (12). However, VEGF is found in a variety of tissues. Mice that lack the VEGF protein or one of the VEGF receptors (VEGF-R) are not viable (13). As of now four different human isoforms of VEGF and three different VEGF receptors have been described (14), wherein Flt-1 (VEGF-R1) and Flk/KDR (VERGF-R2) are receptor tyrosine kinases. [0009] In the mature human lung VEGF is primarily found in alveolar type II cells (13), whereas in the premature human lungs of fetuses VEGF is located in the basal membrane of the airway epithelia. Thus, VEGF probably has an early impact on the vascularization of the airways (14). VEGF stimulates different signal transduction pathways by binding to its receptors, wherein also cross talk takes place. On the one hand, VEGF stimulates the proliferation and migration of blood vessels (VEGF-R1, VEGF-R2), and, on the other hand, VEGF increases the vascular permeability (VEGF-R3). The physiological response to VEGF depends on the dosage of VEGF and on the corresponding receptor distribution (15). [0010] A paracrine mechanism for VEGF function has been postulated. Thus, VEGF can modulate the vascular endothelium, especially when produced by epithelial cells (16). In contrast to these initial findings it has been recently shown, that VEGF does not only influence endothelial cells, but it rather stimulates the proliferation and differentiation of epithelial cells in an autocrine manner (17). The expression of VEGF is variable and depends on various factors, especially the oxygen concentration. The oxygen dependent regulation of VEGF is mostly regulated by the hypoxia inducible factor (HIF) (18). [0011] The pulmonary synthesis of VEGF and VEGF receptor is significantly stimulated by hypoxia (19, 20). During hyperoxia the VEGF production is suppressed. This suppression is considered to be (at least in part) responsible for the oxygen induced toxicity (21, 22). During hyperoxia the VEGF protein production rapidly decreases within the first 48 hours, whereas the concentration of the two receptors VEGF-R1 and VEGF-R2 decreases not until after 48 hours, probably secondarily due to the loss of endothelial cells (21). In a rat model, where the VEGF receptor was chemically blocked and, thus, the VEGF-dependent signal transduction was inhibited, the close relationship between oxidative stress and apoptosis has been demonstrated. Thereby, the oxidative stress led to an increased apoptosis and the subsequent development of a lung emphysema, but an increased apoptosis leads to an increased expression of oxidative stress markers as well (23). [0012] Furthermore, VEGF plays an important role in the pathogenesis of broncho-pulmonary dysplasia of preterm neonates (BPD). Preterm newborns who develop a BPD have a lower VEGF concentration in the tracheal secret in the first days after birth compared to that of an appropriate control group without later BPD (24). In lung autopsy samples of preterm neonates, that had died of BPD, a lower expression of VEGF mRNA, VEGF protein and VEGF receptor in comparison to the control group was found (25). In the thickened alveolar septa of BPD patients the VEGF mRNA is reduced, while at the same time the angiogenic receptors Flt-1 (VEGF-R1) and TIE-2 are reduced as well. This suggests that the morphological changes that are typical for BPD are caused by the perturbed expression of VEGF, VEGF receptor and other angiogenic factors. [0013] Moreover, VEGF mediates an anti-apoptotic effect. VEGF inhibits the TNF.alpha.-induced apoptosis in endothelial cells (26). VEGF mediates anti-apoptotic effects in endothelial cells via extrinsic (receptor-dependent) apoptotic cascades. Besides the influence on the intracellular signalling cascades the regulation of the cytoskeleton by VEGF becomes more important. Furthermore, VEGF induces the expression of the adhesion proteins fibronectin and integrin .beta.3. The loss of their adhesion ability leads to an increased apoptosis and to cell death of endothelial cells (26). VEGF is not only a potent mitogen of the angiogenesis, it further has a protective effect on endothelial cells (15). VEGF induces the expression of the anti-apoptotic proteins Bcl-2 and A1 by activating phosphatidyl-inositol-3 kinase in vascular endothelial cells (27, 28). An antibody directed against VEGF-R1, that inhibits the receptor-mediated effect of VEGF, led to a high apoptosis index, an almost complete inhibition of growth and a high lethality of newborn mice. However, these changes are not found with juvenile and adult mice (29), which may probably be explained by the increased sensibility for VEGF of premature cells. [0014] VEGF has already been used for the treatment of pulmonary hypertension. The U.S. Pat. No. 6,352,975 and the patent applications WO 00/013702 and WO 00/013703 disclose methods for the treatment of salt-sensitive hypertension. These methods involve administering VEGF in an amount effective to reduce the blood pressure of a patient suffering from salt-sensitive hypertension to a normal range. Thereby, the preferred method is that VEGF is co-administered with another angiogenic factor, or two or more VEGF are administered. Furthermore, the VEGF used can contain a heparin binding domain. WO 00/071716 further discloses disulfide-bonded dimeric VEGF useful for the treatment of hypertension. [0015] The patent application WO 00/065043 uses recombinant defective adenovirus comprising a nucleic acid encoding an angiogenic factor, such as VEGF among others, for treating pulmonary arterial hypertension. [0016] Further, the intra-ocular injection of VEGF is used to treat retinopathy of prematurity (ROP), which is initiated by hyperoxia-induced obliteration of newly formed blood vessels in the retina of premature newborns (30). [0017] The patent application WO 02/086497 discloses the use of hypoxia inducible factor 2.alpha. (HIF-2.alpha.) or VEGF for the treatment of pulmonary hypertension and neonatal respiratory distress syndrome (nRDS). Thus, the patients are preterm infants with an immature lung. The immaturity is the reason for a surfactant deficiency and the subsequent respiratory distress. The treatment is carried out either by an intra-amniotical administration to unborn fetuses (i.e. prior to delivery) or an intra-tracheal administration after birth. The proposed effect of the VEGF is the improvement of surfactant production that is supposed to protect the preterm newborns against nRDS. Subsequently, the need for mechanical ventilation will be reduced. However, the proposed treatment is limited to one group of patients which have a surfactant deficiency due to their immature lungs. However, NRDS is already been treated successfully by two different strategies (since more than 10 years): the prenatal induction of lung maturation and the postnatal surfactant substitution. Thus, a replacement of these established therapies is unlikely. [0018] There is a need for a pharmaceutical to treat and furthermore prevent lung injuries, especially chronic damages, in patients of all ages, where lung injury is related to a deregulation of the oxygen provision and is especially caused by high concentrations of inspired oxygen. [0019] The objective has been solved according to the present invention by the use of VEGF for the manufacture of a medicament for the treatment and/or prevention of pulmonary diseases or conditions that are related to high concentrations of inspired oxygen. High concentrations of oxygen are considered as oxygen concentrations higher than in atmospheric air (fraction of inspired oxygen above 0.21). [0020] The term "vascular endothelial growth factor" or "VEGF" as used herein refers to any naturally occurring (native) forms of a VEGF polypeptide (also known as "vascular permeability factor" or "VPF") from any animal species, including humans and other mammalian species, such as murine, bovine, equine, porcine, ovine, canine, or feline, and functional derivatives thereof. "Native human VEGF" consists of two polypeptide chains generally occurring as homodimers. Each monomer occurs as one of five known isoforms, consisting of 121, 145, 165, 189, and 206 amino acid residues in length. These isoforms will be hereinafter referred to as hVEGF.sub.121, hVEGF.sub.145, hVEGF.sub.165, hVEGF.sub.189, and hVEGF.sub.206, respectively. Similarly to the human VEGF, "native murine VEGF" and "native bovine VEGF" are also known to exist in several isoforms, 120, 164, and 188 amino acids in length, usually occurring as homodimers. With the exception of hVEGF.sub.121, all native human VEGF polypeptides are basic, heparin-binding molecules. hVEGF.sub.121 is a weakly acidic polypeptide that does not bind to heparin. These and similar native forms, whether known or hereinafter discovered are all included in the definition of "native VEGF" or "native sequence VEGF", regardless of their mode a preparation, whether isolated from nature, synthesized, produced by methods of recombinant DNA technology, or any combination of these and other techniques. The term "vascular endothelial growth factor" or "VEGF" includes VEGF polypeptides in monomeric, homodimeric and heterodimeric forms. The definition of "VEGF" also includes a 110 amino acids long human VEGF species (hVEGF.sub.110), and its homologues in other mammalian species, such as murine, bovine, equine, porcine, ovine, canine, or feline, and functional derivatives thereof. In addition, the term "VEGF" covers chimeric, dimeric proteins, in which a portion of the primary amino acid structure corresponds to a portion of either the A-chain subunit or the B-chain subunit of platelet-derived growth factor, add a portion of the primary amino acid structure corresponds to a portion of vascular endothelial growth factor. In a particular embodiment, a chimeric molecule is provided consisting of one chain comprising at least a portion of the A- or B-chain subunit of a platelet-derived growth factor, disulfide linked to a second chain comprising at least a portion of a VEGF molecule. More details of such dimers are provided, for example, in U.S. Pat. Nos. 5,194,596 and 5,219,739 and in European Patent EP-B 0 484 401, the disclosures of which are hereby expressly incorporated by reference. The nucleotide and amino acid sequences of hVEGF.sub.121 and bovine VEGF.sub.120 are disclosed, for example, in U.S. Pat. Nos. 5,194,596 and 5,219,739, and in EP 0 484 401. hVEGF.sub.145 is described in PCT Publication No. WO 98/10071; hVEGF.sub.165 is described in U.S. Pat. No. 5,332,671; hVEGF.sub.189 is described in U.S. Pat. No. 5,240,848; and hVEGF.sub.206 is described in Houck et al. Mol. Endocrinol. 5:1806-1814 (1991). Other VEGF polypeptides and polynucleotides have been described, including, for example, zvegf2 (PCT Publication No. WO 98/24811), and VRP (PCT Publication No. WO 97/09427), and are also encompassed by the term VEGF. For the disclosure of the nucleotide and amino acid sequences of various human VEGF isoforms see also Leung et al., Science 246:1306-1309 (1989); Keck et al., Science 246:1309-1312 (1989); Tisher et al., J. Biol. Chem. 266:11947-11954 (1991); EP 0 370 989; and PCT publication WO 98/10071. For further review, see also Klagsbum and D'Amore, Cytokine and Growth Factor Reviews 7:259-170 (1996). [0021] The term "VEGF" encompasses a polypeptide having an amino acid sequence substantially homologous to one or more of the above-mentioned native VEGF polypeptides, and which retains a biological activity associated with VEGF. An amino acid sequence is considered to be "substantially homologous" herein if the level of amino acid sequence homology is at least about 50%, preferably at least about 80%, more preferably at least about 90%, most preferably, at least about 95%, compared with the native VEGF protein in question. [0022] Also included within the scope of "VEGF" herein are biologically active fragments thereof, as well as N-terminally or C-terminally extended versions thereof or analogs thereof substituting and/or deleting or inserting one or more amino acid residues which retain qualitatively the biological activities of the protein described herein. [0023] The term "VEGF" specifically includes homodimeric and heterodimeric forms of the VEGF molecule, in which the dimer is formed via interchain disulfide bonds between two subunits. Homodimers may have both of their subunits unglycosylated or glycosylated, while in heterodimers, one subunit may be glycosylated and the other unglycosylated. The term "VEGF" specifically includes not only amino acid sequence variants but also glycosylation variants of the native VEGF molecules. [0024] In addition, the term "VEGF" covers chimeric, dimeric proteins, in which a portion of the primary amino acid structure corresponds to a portion of either the A-chain subunit or the B-chain subunit of platelet-derived growth factor, add a portion of the primary amino acid structure corresponds to a portion of vascular endothelial growth factor. Continue reading... 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